Transient TNF regulates the self-renewing capacity of stem-like label-retaining cells in sphere and skin equivalent models of melanoma.

International audience: BackgroundIt is well established that inflammation promotes cancer, including melanoma, although the exact mechanisms involved are less known. In this study, we tested the hypothesis that inflammatory factors affect the cancer stem cell (CSC) compartment responsible for tumor development and relapse.ResultsUsing an inducible histone 2B-GFP fusion protein as a tracer of cell divisional history, we determined that tumor necrosis factor (TNF), which is a classical pro-inflammatory cytokine, enlarged the CSC pool of GFP-positive label-retaining cells (LRCs) in tumor-like melanospheres. Although these cells acquired melanoma stem cell markers, including ABCB5 and CD271, and self-renewal ability, they lost their capacity to differentiate, as evidenced by the diminished MelanA expression in melanosphere cells and the loss of pigmentation in a skin equivalent model of human melanoma. The undifferentiated cell phenotype could be reversed by LY294002, which is an inhibitor of the PI3K/AKT signaling pathway, and this reversal was accompanied by a significant reduction in CSC phenotypic markers and functional properties. Importantly, the changes induced by a transient exposure to TNF were long-lasting and observed for many generations after TNF withdrawal.ConclusionsWe conclude that pro-inflammatory TNF targets the quiescent/slow-cycling melanoma SC compartment and promotes PI3K/AKT-driven expansion of melanoma SCs most likely by preventing their asymmetrical self-renewal. This TNF effect is maintained and transferred to descendants of LRC CSCs and is manifested in the absence of TNF, suggesting that a transient exposure to inflammatory factors imprints long-lasting molecular and/or cellular changes with functional consequences long after inflammatory signal suppression. Clinically, these results may translate into an inflammation-triggered accumulation of quiescent/slow-cycling CSCs and a post-inflammatory onset of an aggressive tumor

Brain metastasis and renal cell carcinoma : prognostic scores assessment in the era of targeted therapies

Aim: This study aimed at exploring several brain metastatic prognostic scores in patients with renal cell carcinoma. Patients and Methods: We retrospectively analyzed data of 93 metastatic renal cell carcinoma patients who were diagnosed with brain metastases between October 2005 and July 2016 who received targeted therapy. Potential prognostic factors (RTOG RPA, BS-BM, and a newly developed score CERENAL) were analyzed. Results: A total of 75 patients received targeted therapy. All scores showed prognostic value in progression-free survival after first-line treatment with CERENAL being the sole independent prognostic factor associated with improved duration of first-line treatment. Both RTOG RPA and CERENAL were potential prognosticators for overall survival, whereas only the CERENAL score was associated with prolonged disease-specific survival. Conclusion: Several prognostic scores can be useful to predict survival of patients with brain metastases from renal cancer, especially the newly developed CERENAL score

Safety and Efficacy of Durvalumab With or Without Tremelimumab in Patients With PD-L1-Low/Negative Recurrent or Metastatic HNSCC The Phase 2 CONDOR Randomized Clinical Trial

IMPORTANCE: Dual blockade of programmed death ligand 1(PD-L1) and cytotoxic T-lymphocyte associated protein 4 (CTLA-4) may overcome immune checkpoint inhibition. It is unknown whether dual blockade can potentiate antitumor activity without compromising safety in patients with recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC) and low or no PD-L1 tumor cell expression. OBJECTIVE :To assess safety and objective response rate of durvalumab combined with tremelimumab. DESIGN, SETTING, AND PARTICIPANTS: The CONDOR study was a phase 2, randomized, open-label study of Durvalumab, Tremelimumab, and Durvalumab in Combination With Tremelimumab in Patients With R/M HNSCC. Eligibility criteria included PD-L1-low/negative disease that had progressed after 1 platinum-containing regimen in the R/M setting. Patients were randomized (N = 267) from April 15, 2015, to March 16, 2016, at 127 sites in North America, Europe, and Asia Pacific. INTERVENTIONS: Durvalumab (20 mg/kg every 4 weeks) + tremelimumab (1 mg/kg every 4 weeks) for 4 cycles, followed by durvalumab (10 mg/kg every 2 weeks), or durvalumab (10 mg/kg every 2 weeks) monotherapy, or tremelimumab (10 mg/kg every 4 weeks for 7 doses then every 12 weeks for 2 doses) monotherapy. MAIN OUTCOMES AND MEASURES: Safety and tolerability and efficacy measured by objective response rate. RESULTS: Among the 267 patients (220 men [82.4%]), median age (range) of patients was 61.0 (23-82) years. Grade 3/4 treatment-related adverse events occurred in 21 patients (15.8%) treated with durvalumab + tremelimumab, 8 (12.3%) treated with durvalumab, and 11 (16.9%) treated with tremelimumab. Grade 3/4 immune-mediated adverse events occurred in 8 patients (6.0%) in the combination arm only. Objective response rate (95% CI) was 7.8% (3.78%1339%) in the combination arm (n =129), 9.2% (3.46%-19.02%) for durvalumab monotherapy (n = 65), and 1.6% (0.04%-8.53%) for tremelimumab monotherapy (n = 63); median overall survival (95% CI) for all patients treated was 7.6 (4.9-10.6), 6.0 (4.0-11.3), and 5.5 (3.9-7.0) months, respectively. CONCLUSIONS AND RELEVANCE: In patients with R/M HNSCC and low or no PD-Lt tumor cell expression, all 3 regimens exhibited a manageable toxicity profile. Durvalumab and durvalumab + tremelimumab resulted in clinical benefit, with minimal observed difference between the two. A phase 3 study is under way

Tackling the challenges of brain metastases in solid tumors

SCOPUS: ed.jinfo:eu-repo/semantics/publishe

Etude de la cardiotoxicité au cours et à distance du traitement du cancer du sein par chimiothérapie adjuvante ou néoadjuvante associée au trastuzumab chez les patientes Her2 positives

LILLE2-BU Santé-Recherche (593502101) / SudocSudocFranceF

Eribulin in the soft tissue sarcoma therapeutic landscape: Little is good, then more is better

SCOPUS: no.jinfo:eu-repo/semantics/publishe

Metabolic disorders associated with the use of targeted cancer therapies

Purpose of review The everyday use of targeted therapies, whose mechanisms of action differ from the conventional cytotoxic agents, also causes the emergence of new toxicities as metabolic disorders about which little is known. We propose a systematic literature review of the incidence and physiopathology of targeted therapies-induced metabolic disorders and provide some management guidance. Recent findings In recent decades, significant breakthroughs in molecular oncology and immunology have been made. The administration of targeted therapies and immunotherapy has been associated with metabolic toxicities such as endocrine disorders, dyslipidemia, induced diabetes, and electrolytic disorders. Current data show that metabolic disorders are becoming increasingly common, but rarely life threatening and often reversible with prompt therapeutic intervention. Summary In the era of targeted therapies, medical oncologists should know the symptoms, carefully monitor patients for potential metabolic disorders, and manage these emerging side-effects with the help of endocrinologists and other medical specialists.SCOPUS: re.jinfo:eu-repo/semantics/publishe

How to emerge from the conservatism in clinical research methodology?

Purpose of review Despite recent changes in clinical research methodology, many challenges remain in drug development methodology. Recent findings Advances in molecular biology and cancer treatments have changed the clinical research landscape. Thus, we moved from empirical clinical oncology to molecular and immunological therapeutic approaches. Along with this move, adapted dose-limiting toxicities definitions, endpoints, and dose escalation methods have been proposed. Moreover, the classical frontier between phase I, phase II, and phase III has become unclear in particular for immunological approaches. So, investigators are facing major challenges in drug development methodology. Summary We propose to individualize clinical research using innovative approaches to significantly improve patient outcomes and targeting what is considered unmet need. Integrating high level of translational research and performing well designed biomarker studies with great potential for clinical practice are of utmost importance. This could be performed within new models of clinical research networks and by building a strong collaboration between academic, cooperative groups, on-site investigators, and pharma.SCOPUS: re.jinfo:eu-repo/semantics/publishe

New horizons in early drugs development in solid cancers

PURPOSE OF REVIEW: Drug development is the process of bringing new anticancer agents into clinical practice. From the basic research to clinical research each step is essential and intimately linked. The aim of this review is to describe emerging preclinical models and to provide an overview of selected drugs recently developed in oncology. RECENT FINDINGS: Preclinical models reproducing human immune-tumor interactions, 3D cell cultures and microfluidic platforms are of great interest for the development of immunotherapies and combination therapies and offer the opportunity to better understand the interplay between cancer and stromal cells.Following a better biological understanding of cancer and advances in precision oncology, new exciting drugs (e.g. antibodies-drugs conjugates [ADCs], immunotherapeutic strategies, molecular-targeted therapies) have entered the field of clinical research and even clinical practice. SUMMARY: Recent improvements in preclinical models will allow an accurate selection of drug candidates for clinical research. Innovative drugs are currently being developed from early to later phases of development. An important remaining challenge in drug development is to set up a new model of patient-centered clinical research to facilitate quick access to innovation and target-oriented trials.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Therapy of breast cancer brain metastases: challenges, emerging treatments and perspectives

Brain metastases are the most common central nervous system tumors in adults, and incidence of brain metastases is increasing due to both improved diagnostic techniques (e.g. magnetic resonance imaging) and increased cancer patient survival through advanced systemic treatments. Outcomes of patients remain disappointing and treatment options are limited, usually involving multimodality approaches. Brain metastases represent an unmet medical need in solid tumor care, especially in breast cancer, where brain metastases are frequent and result in impaired quality of life and death. Challenges in the management of brain metastases have been highlighted in this review. Innovative research and treatment strategies, including prevention approaches and emerging systemic treatment options for brain metastases of breast cancer, are further discussed